Abstract
Berberine (BBR) has been explored as a potential anti-liver fibrosis agent, but the underlying mechanisms are unknown. In the current study, we aimed to investigate the molecular mechanisms underlying the effect of BBR against liver fibrogenesis in thioacetamide (TAA) and carbon tetrachloride (CCl4) induced mouse liver fibrosis. In addition to i.p. injection with TAA or CCl4, mice in the treatment group received BBR intragastrically. Concurrently, combined with TAA and BBR treatment, mice in the inhibitor group were injected i.p. with ferrostatin-1 (Fer-1). Hepatic stellate cells (HSCs) were also used in the study. Our results showed that BBR obviously alleviated mouse liver fibrosis and restored mouse liver function; however, the pharmacological effects of BBR against liver fibrosis were significantly diminished by Fer-1 treatment. Mechanically, BBR impaired the autophagy–lysosome pathway (ALP) and increased cell reactive oxygen species (ROS) production in HSCs. ROS accelerated the breakdown of the iron-storage protein ferritin and sped up iron release from ferritin, which resulted in redox-active iron accumulation in HSCs. Lipid peroxidation and glutathione (GSH) depletion triggered by the Fenton reaction promoted ferroptosis and attenuated liver fibrosis. Furthermore, impaired autophagy enhanced BBR-mediated ferritin proteolysis to increase cellular ferrous overload via the ubiquitin–proteasome pathway (UPS) in HSCs and triggered HSC ferroptosis. Collectively, BBR alleviated liver fibrosis by inducing ferrous redox to activate ROS-mediated HSC ferroptosis. Our findings may be exploited clinically to provide a potential novel therapeutic strategy for liver fibrosis.
Highlights
Liver fibrosis is a growing global health problem characterized by activated hepatic stellate cells (HSCs) and excess deposition of fibrillary collagen [1]
Liver fibrosis is a dynamic process of chronic liver inflammation characterized by net accumulation of extracellular matrix (ECM) [1]
We found that BBR treatment rescued liver fibrosis by inducing HSC ferroptosis
Summary
Liver fibrosis is a growing global health problem characterized by activated hepatic stellate cells (HSCs) and excess deposition of fibrillary collagen [1]. Regulation of the activation and targeted scavenging of HSCs requires new targets for treatment and to reverse fibrogenesis; there is currently a lack of effective methods. Our previous work showed that targeted deletion of ARRB1 in mice alleviated liver fibrosis by modulating autophagy [3]; other effects of dysfunctional HSC cells, including induction of apoptosis [4], lipocyte phenotype [5], and glycolytic function [6], could mitigate the pathological morphological changes in liver fibrosis. BBR was found to inhibit HSC proliferation and extracellular matrix (ECM) production, alleviating liver fibrosis [10]. Despite the positive outcomes, its underlying mechanism has not been elucidated
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